i) Field of the Invention
This invention relates to novel processes for preparing substituted pyrrolizine compounds. More particularly, it relates to novel processes for preparing 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate of the following formula (I) from pyrrole. ##STR2##
By hydrolysis and/or mono-decarboxylation from the compounds of formula (I), the useful anti-inflammatory agent and analgesic agent can be prepared.
ii) Description of the Prior Art
5-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (hereinafter referred to as ketorolac) was first synthesized and patented under the U.S. Pat. No. 4,089,969 by Muchowsky in 1978. The following formula (II) and its pharmaceutically acceptable salts and esters are now under study as analgesic, anti-inflammatory and anti-pyretic agents for humans. Further, they can be also used for muscle relaxants. ##STR3##
Currently, ketorolac has been marketed as useful a anti-inflammatory agent and analgestic agent in the United States, Italy, the Netherlands and other nations.
Various methods for preparing the pyrrolizine derivatives including ketorolac were disclosed by U.S. Pat. Nos. 4,347,186; 4,458,081; 4,347,187; 4,454,326; 4,347,185; 4,505,927; 4,456,759; 4,873,340; 4,496,741; 5,082,950 and 5,082,951.
In U.S. Pat. No. 4,317,186, a fundamental approach to the synthesis of 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylates of formula (I) was disclosed. In this process, the crucial step was the intramolecular displacement of methanesulfinate ion by sodium malonates. However, this preparation method has some drawbacks due to its long reaction pathway and low yield of end product.
The following are reaction schemes of this method: ##STR4## wherein R.sup.3 and X are independently hydrogen or lower alkyl; and
Ar is a moiety selected from the group consisting of furyl or thienyl derivatives substituted by hydrogen, methyl, chloro or bromo; phenyl derivatives substitated by hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkyl carbonyl, fluoro, chloro or bromo; and pyrrolyl derivatives substituted by hydrogen or lower alkyl. PA1 Ar is a moiety selected from the group consisting of phenyl derivatives substituted by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, dialkylamine, hydrogen, hydroxy, phenyl, phenyloxy, benzyl, benzoyl and nitro radical at any available position in the aromatic ring; PA1 X is selected from the group consisting of alkoxycarbonyl, acyloxy and hydrogen. PA1 X is hydrogen or alkoxycarbonyl; PA1 Ar is a moiety selected from the group consisting of ##STR7## in which; R.sup.2 is hydrogen, methyl, chloro or bromo, the R.sup.2 substitution being at the 3-, 4- or 5-position of the ring; PA1 R.sup.3 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkylcarbonyl, fluoro, chloro or bromo, the R.sup.3 substitution being at any available position in the ring; PA1 R.sup.4 is hydrogen or lower alkyl; PA1 Y is oxygen or sulfur. PA1 X is hydrogen or alkoxycarbonyl; PA1 Ar is a moiety selected from the group consisting of ##STR9## in which; R.sup.2 is hydrogen, methyl, chloro or bromo, the R.sup.2 substitution being at the 3-, 4- or 5-position of the ring; PA1 R.sup.3 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkylcarbonyl, fluoro, chloro or bromo, the R.sup.3 substitution being at any available position in the ring; PA1 R.sup.4 is hydrogen or lower alkyl; and PA1 Y is oxygen or sulfur.
Another method for preparing the compounds of formula (I) was disclosed in U.S. Pat. No. 5,082,950 by Muchowski using the intermolecular double alkylation reaction. However, it requires excessive reagents for the reaction, even though the reaction pathway becomes short.
The following are reaction schemes disclosed in U.S. Pat. No. 5,082,950: ##STR5## wherein R is lower alkyl;